Genetic, Transcriptome, Proteomic, and Epidemiological Evidence for Blood-Brain Barrier Disruption and Polymicrobial Brain Invasion as Determinant Factors in Alzheimer’s Disease

Carter, Chris J.

The APOE4 variant is also associated with enhanced immune/inflammatory responses. TLR activation (TLR3, 4) in microglia induces cyclooxygenase-2 (PTGS2), microsomal prostaglandin E synthase (PTGES), and prostaglandin E2, an effect exaggerated in APOE4 (+/+) mice [132] . APOE4 is also associated with enhanced in vivo innate immune responses in human subjects. Whole blood from healthy APOE3/APOE4 volunteers induced higher cytokine levels on ex vivo stimulation with TLRs (TLR2, 4, or 5) ligands than blood from APOE3/APOE3 patients [133] . Gain of function also applies to AD variant forms of complement receptor CR1, which are better able to bind complement component C1q or C3B [134] . C1q and C3B are opsonins that interact with complement cell-surface receptors (C1qRp, CR1, CR3, and CR4) to promote phagocytosis (including that of infectious agents) and a local pro-inflammatory response [135] . TREM2 variants in AD are also associated with enhanced inflammatory responses (upregulation of proinflammatory cytokines) [136] . In presenilin (PSEN1) mutant knockin mice, microglial challenge with bacterial LPS results in enhanced nitric oxide and inflammatory cytokine responses, relative to normal mice [137] . For these genes at least, this gain of immune/inflammatory function concords with selection for pathogen resistance.